Abstract
Antioxidant collagen hydrolysates refers to the peptides mixture with antioxidant properties identified from hydrolyzed collagen. Due to its specific structural, biological and physicochemical properties, collagen hydrolysates have been explored as a multifunctional antioxidant in the biomedical field. In this review, we summarize recent advances in antioxidant collagen hydrolysates development. Initially, the preparation process of antioxidant collagen hydrolysates is introduced, including the production and separation methods. Then the effects and the mechanisms of amino acid composition and collagen peptide structure on the antioxidant activity of collagen hydrolysates are reviewed. Finally, the applications of antioxidant collagen hydrolysates in biomedical domains are summarized, with critical discussions about the advantages, current limitations and challenges to be resolved in the future.
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1 Introduction
Oxidative stress is caused by excessive production and accumulation of reactive oxygen species (ROS) in cells and tissues. ROS are usually produced in the cells of living organisms as a result of normal cellular metabolism and are fundamental to maintaining cellular homeostasis. Common ROS include superoxide radicals (O2·−) and hydrogen peroxide (H2O2) [1]. While a basal concentration of ROS is indispensable for the manifestation of cellular functions, excessive levels of ROS cause damage to cellular macromolecules such as DNA, lipids, and proteins, eventually leading to necrosis and apoptotic cell death, which has harmful effects on tissues [2]. It explains why oxidative stress is detrimental to human health. When oxidative stress occurs, the balance of the redox system is damaged, resulting in the accumulation of a large number of intracellular oxidation products, which may be associated with accelerated aging, neurodegeneration, inflammation, tumor, diabetes, and other diseases [3,4,5,2.4.1 Ultrafiltration The first step in the purification process of antioxidant collagen hydrolysates is usually ultrafiltration membrane separation, due to its advantage of simple operation, low energy consumption and environmental friendliness [63]. Furthermore, ultrafiltration is an effective purification method to obtain low molecular weight peptides from crude hydrolysates. Reportedly, these low molecular weight peptides (2–20 amino acids) are more biologically active than their larger polypeptide/proteins counterparts. For example, Norizah et al. [64] separated three antioxidant peptide components from chicken skin gelatin hydrolysate by using different ultrafiltration membranes (Mw = 10, 5, 2 kDa, respectively). The low molecular weight (Mw < 2 kDa) peptides showed better antioxidant properties than the original gelatin hydrolysate stock solution. Hong et al. [65] obtained the antioxidant collagen hydrolysate (Mw < 3 kDa) with collagenase inhibition effects comparable to vitamin C through ultrafiltration, which may play an important role in anti-aging activities. They proved that the degree of hydrolysis (DH) may significantly affect the molecular weight and the exposure of the terminal amino groups of the resulting product [65]. Nevertheless, many studies have shown that molecular weight was not directly correlated with antioxidant activity. Table 1 summarizes the molecular weights of some antioxidant collagen hydrolysates used in biomedical applications. For example, some antioxidant collagen peptides with approximate molecular weight, GRW(417.46 Da) and GPGPT(427.45 Da), showed different antioxidant capacities [33]. It has been also noted that some high molecular weight antioxidant collagen hydrolysates also demonstrated the potential to prevent or treat diseases associated with oxidative stress [31]. Although the molecular weight of antioxidant collagen hydrolysate from bigeye tuna bone (DH = 21.96 ± 0.16%) is greater than that from bigeye tuna skin (DH = 34.28 ± 0.44%), the bone collagen hydrolysate showed better anti-photoaging effects [28]. This can be explained by the differences in the amino acid sequence of the peptides rather than of DH [66, 67]. Although ultrafiltration is useful in separating antioxidant collagen hydrolysates with low molecular weight, it may cause a reduction in yield. Nowadays, more and more studies combine ultrafiltration with chromatography to separate collagen hydrolysates and obtain components with higher antioxidant activity [42]. Chromatography has played a key role in the purification of antioxidant collagen hydrolysates for decades. The principle of chromatography technology is based on the differences in the physical and chemical properties of the mixed peptide components, so that they are distributed differently in the fixed phase and the mobile phase, so as to achieve the purpose of separation. The common chromatographic separation technologies for separating and purifying the biomedical antioxidant collagen hydrolysates mainly include gel filtration chromatography (GFC), ion-exchange chromatography (IEC), and reverse-phase high-performance liquid chromatography (RP-HPLC), etc. [32, 42, 68] The separation principles, advantages and disadvantages of these common chromatographic separation techniques are shown in Table 2. Gel filtration chromatography (GFC) is also known as molecular sieve or particle size exclusion chromatography. As mentioned in Table 2, the separation principle of GFC is based on the molecular size of peptides or proteins. The separation efficiency of this technology is mainly affected by many factors, such as packing type and the column volume. The method has the advantages of simple operation, no pollution, low cost, and has been widely used in the purification of antioxidant collagen hydrolysates. Generally, GFC is used to obtain low molecular weight peptides. Low molecular weight peptides have been found to exhibit potent antioxidant activity compared to larger peptides and proteins [23]. This is primarily due to their ability to easily enter into the oxidant/antioxidant system, allowing them to interact with reactive oxygen species (ROS) and terminate free radical chain reactions. It has been proved that the antioxidant activity of collagen hydrolysate obtained by gel filtration increase by two folds compared with the unseparated collagen hydrolysates, and the antioxidant activity of small molecular weight collagen hydrolysate obtained by gel filtration is better than that of the unseparated collagen hydrolysates in most cases [72]. The application of ion-exchange chromatography (IEC) in the separation, structure determination, and detection of proteins and peptides has been increased. IEC can separate and purify biologically active collagen peptides according to their net charges. By adjusting pH, the net charge of collagen peptides is tunable, thereby making them easily separated by IEC. For example, Banerjee et al. [73] separated and purified a collagen hydrolysate with high antioxidant properties from bovine Achilles tendon by IEC, which has the potential to act as an antioxidant in case of a free radical overload for human health. Furthermore, the combination of IEC and GFC has been used for the separation of collagen hydrolysates to improve antioxidant activity against fatigue caused by oxidative stress [74]. This is due to certain low molecular weight peptides containing charged residues such as Glu, Lys, and Arg have been shown to possess antioxidant and metal-chelating activity [75]. This metal-chelating ability is particularly important in preventing metal ion-induced oxidative stress. The composition of amino acids in peptides also play a significant role in their antioxidant activity. Peptides containing acidic and basic amino acids have been reported to exhibit excellent antioxidant properties [76]. These amino acids can contribute to the chelation of metal ions, scavenge free radicals, and inhibit oxidative damage. However, this technique has disadvantages, including cost-effectiveness, method complexity, and sensitivity toward pH and metal ions [81]. Oxidative stress perpetuates the cycle of destruction at the root of retina diseases. Application of collagen mimetic peptides reduced production of ROS and improve retinal pigment epithelium cells adherence and survival by repairing collagen damaged [118]. In H2O2 simulated in vitro oxidative stress microenvironment, carboxymethyl cellulose modified with collagen peptide (CMCC) showed antioxidant capacity, which can effectively inhibit ROS production in rat retinal endothelial cells. In addition, CMCC, as a drug carrier, significantly reduced the retinal oxidative stress level and potently recovered the activities of typical antioxidant enzymes, SOD and CAT in the retina of mice after loading anti-inflammatory drugs [119]. Acute kidney injury (AKI) is common in critically ill patients and can lead to chronic kidney disease when left untreated. Inflammation and oxidative stress play the key role in the development of AKI. In the nucleus, the expression of antioxidant enzymes such as SOD, heme oxygenase-1 (HO-1), CAT, and GSH-Px is stimulated by the binding of the activated Nrf2 and the antioxidant response element [120]. A case study has reported that collagen hydrolysate from Acaudina molpadioides could activate the NF-κB and Nrf2 pathway through the PI3K/AKT pathway to protect kidney from damage caused by oxidative stress, which laid a foundation for the application of collagen hydrolysate in the prevention of AKI [61].2.4.2 Chromatography separation technology
5 Summary and outlook
In summary, the present review provided an update on antioxidant collagen hydrolysates development in recent years. As elaborated in this review, antioxidant collagen hydrolysates, as collagen derivatives from natural resources, shows great potential for current and future biomedical applications. Previous studies demonstrated an increasing number of antioxidant collagen hydrolysates investigations against several diseases and disorders. These studies advanced the development of extraction and isolation techniques, revealed the structure–activity relationship between peptide and target protein catalytic sites, and explored the mechanisms of antioxidant collagen hydrolysates treating different diseases. As a result, we believe that such efforts will promote further interests in versatile antioxidant collagen hydrolysates.
Regarding future directions in this field, obtaining highly active antioxidant collagen hydrolysates is crucial to realize its therapeutic potential. This could be achieved by develo** new enzymes for the hydrolysate preparation. By exposing key amino acid residues with antioxidant contribution in the final peptides, it is possible to enhance the antioxidation capability of the hydrolyzed collagen peptides obtained from the same raw material. Furthermore, we need a more comprehensive understanding of the structure–function relationship of collagen hydrolysates. In the future, the identification of antioxidant collagen hydrolysates should not only clarify the amino acid sequence, but also clarify the secondary structure. Due to the immense number of peptide combinations in antioxidant collagen hydrolysates, advances in the elaboration and constant update of databases regarding the peptides formed in proteolytic reactions are necessary. Prediction of possible products and the consequent biological activity is using computational simulation may improve the selection and production of new antioxidant collagen hydrolysates/peptides. In addition, it is highly recommended that researchers specify the species, and possibly the breed, of the selected collagen in their research, as this provides additional evidence for comparing the antioxidant potential of collagen hydrolysates from different animals.
For biomedical applications, the antioxidant effects reported in the in vivo and in vitro studies underscore the importance of collagen hydrolysates for the removal and defense against reactive substances such as ROS. Further research is needed to assess the efficacy and reproducibility in clinical trials in healthy subjects and patients with oxidative imbalance-related diseases, and to identify and develop preventive and therapeutic measures. Moreover, efforts should be dedicated to develo** safety assessment methods to characterize the toxicological effects of antioxidant collagen hydrolysates before and during clinical trials to anticipate and prevent side effects.
Availability of data and materials
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Abbreviations
- ROS:
-
Reactive oxygen species
- O2 •− :
-
Superoxide radicals
- H2O2 :
-
Hydrogen peroxide
- SOD :
-
Superoxide dismutase
- CAT :
-
Catalase
- GSH-Px :
-
Glutathione peroxidase
- GSH :
-
The glutathione
- MMPs :
-
Collagenase-type matrix metalloproteinases
- DH :
-
The degree of hydrolysis
- GFC, IEC:
-
Gel filtration chromatography, ion-exchange chromatography
- RP-HPLC:
-
Reverse-phase high-performance liquid chromatography
- BLAST:
-
Basic local alignment search tool
- UV:
-
Ultraviolet
- MAPK:
-
Mitogen-activated protein kinase
- ECM:
-
Extracellular matrix
- TGF-β:
-
Transforming growth factor β
- HDF:
-
Human dermal fibroblasts
- MEFs:
-
Mouse embryonic fibroblasts
- HUVECs:
-
Human umbilical vein endothelial cells
- ACE:
-
Angiotensin-I-converting enzyme
- ANG II:
-
Angiotensin II
- eNOS:
-
Endothelial nitric oxide synthase
- AS:
-
Atherosclerosis
- HAECs:
-
Human aortic endothelial cells
- IL3RA:
-
Interleukin-3 receptor subunit alpha
- OA:
-
Osteoarthritis
- AKI:
-
Acute kidney injury
- HO-1:
-
Heme oxygenase-1
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Acknowledgements
Dr. S. Wang acknowledges the financial support from the Academy of Finland (grant no. 331106).
Funding
This work was supported by grants from the National Natural Science Foundation of China (No. 52242208).
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GD contributed to the conceptualization, investigation, formal analysis, visualization, and writing—original draft. KH contributed to investigation, formal analysis, and writing—original draft. XJ contributed to formal analysis and writing—original draft. KW contributed to the writing-original draft preparation and investigation. ZS contributed to the figure preparation. YS contributed to literature filtration. CL and SZ contributions to writing-review and editing of this review. SW, and YH made vital contributions to the conceptualization, methodology, and writing-review and editing of this review. All authors have read and agreed to the published version of the manuscript.
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Yaqin Huang is a member of the editorial board of Collagen and Leather, and was not involved in the editorial review, or the decision to publish this article. All authors declare that there are no competing interests.
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Deng, G., Huang, K., Jiang, X. et al. Developments for collagen hydrolysates as a multifunctional antioxidant in biomedical domains. Collagen & Leather 5, 26 (2023). https://doi.org/10.1186/s42825-023-00131-9
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DOI: https://doi.org/10.1186/s42825-023-00131-9